Simtuzumab for Primary Sclerosing Cholangitis: Phase 2 Study Results With Insights on the Natural History of the Disease

Abstract

Treatment with the LOXL2 inhibitor simtuzumab for 96 weeks did not provide clinical benefit in patients with PSC. This article is protected by copyright. All rights reserved.

Emerging therapies in primary sclerosing cholangitis: pathophysiological basis and clinical opportunities

“…Regardless of the order of mentioned pathophysiological events or the initiating factors, a final common pathway of cellular crosstalk leads to activation of stellate cells (and possibly portal myofibroblasts) with fibrosis, collagen deposition and generation of the scar tissue causing the bile duct strictures [54,55], processes revealing targets for antifibrotic therapy [56][57][58]. The relative importance of the many elements believed to contribute to PSC development and progression is unknown and may vary between subgroups of patients and depending on disease stage (early disease likely to yield other opportunities for therapy than late stage disease).…”

“…LOXL2 activity induction was reported in fibrotic liver diseases including PSC and hepatic and serum LOXL2 levels correlated with fibrosis in PSC [56,180,181]; hence LOXL2 appeared to be an attractive target for therapy. In a phase II clinical trial, patients with compensated PSC (n = 234; half of which had bridging fibrosis or cirrhosis at baseline) were randomized to treatment with simtuzumab 75 mg, 125 mg or placebo for 96 weeks [57]. Results were disappointing, however, for the primary endpoint, showing no effect on fibrosis as assessed by hepatic collagen content.…”

Novel Therapies for Managing Cholestasis

“…As mentioned earlier, OCA has demonstrated antifibrotic properties in animal experiments and in a small subset of patients participating in the POISE trial. Simtuzumab, a monoclonal antibody against lysyl oxidase‐like 2 (LOXL2), was evaluated in a 2‐year phase 2 study for PSC and did not show a benefit in improving fibrosis or reducing PSC‐related clinical events . The FXR agonist cilofexor is under evaluation for PSC, with regression of fibrosis as a primary study endpoint.…”

Is This the Last Requiem for Simtuzumab?

“…Simtuzumab administrated in two different doses over 96 weeks surprisingly did not even show an effect on liver fibrosis, as determined with various tests including measurement of hepatic collagen content. (6) Thus, the list of studies where an anti-LOXL2 strategy with simtuzumab in different diseases failed is growing. These studies, including liver fibrosis due to chronic hepatitis C or nonalcoholic steatohepatitis, pancreas cancer, and lung fibrosis, provided negative results despite successful preclinical studies with antimouse/rat-LOXL2 antibodies in various animal models for such diseases.…”

“…However, the carefully performed placebo‐controlled phase 2b trial of simtuzumab presented by Muir et al in this issue of Hepatology failed to show any clinical benefit. Simtuzumab administrated in two different doses over 96 weeks surprisingly did not even show an effect on liver fibrosis, as determined with various tests including measurement of hepatic collagen content . Thus, the list of studies where an anti‐LOXL2 strategy with simtuzumab in different diseases failed is growing.…”